Anyone with PEMT TT allele (45% of Europeans, only 5% Japanese) is unable to efficiently synthesize phosphatidylcholine (PC) in the liver. PC is needed to.maontaon neuron cell wall integrity
So getting PC from eggs should be very protective for for a big chunk of the population.
I supplement lecithin and citicholine to avoid having to eat eggs every day!
www.preprints.org/manuscript/202512.2694
Any thoughts? Seems like it could suggest something big here?
This is the first RCT to demonstrate significant cognitive reversal (improvement from baseline) rather than just a slowing of decline in a symptomatic population using a personalized, multi-domain protocol. It provides the first randomized evidence for the efficacy of āsystems medicineā in neurology, showing effect sizes 4ā7 times larger than current anti-amyloid monoclonal antibodies.
Blinding: This was an open-label trial for patients and physicians. While raters were blinded, the āattention biasā (PM patients received much more clinical interaction) is a major confounding variable.
Preprint Status: The data has not survived the rigors of peer review at the time of this analysis.
MRI Volumetrics: Despite cognitive gains, there were no significant differences between groups in brain volume changes (e.g., hippocampal volume) over the 9-month period.
Sample Size and Diversity: The cohort was small (N=66 completers) and racially homogenous (92% White), limiting generalizability to broader populations.
Selection Bias: Participants were highly motivated āwellness seekers,ā which may not reflect the average patientās ability to adhere to such a demanding protocol.
Missing Data: A formal assessment of āactivities of daily livingā (adaptive functioning) was omitted.
Thanks for sharing.
The MOCA score (higher is better) should not increase over time in the standard of care group. Similar problem with the brain training. Combined with the absence of significant positive effect on neuroimaging, this suggest a strong placebo effect / intervention bias, in a highly motivated population of people trying to prevent cognitive decline.
Then when you google Bredesen the first result that comes out is: Bredesen Protocol offers false hope of reversing Alzheimerās disease | Alzheimer Society of BC and Yukon
And the principal investigators are all random longevity / functional doctors: https://www.dementiareversaltrial.com/investigators
Thereās a total of 100 interventions (!), the risk of bias is insane.
Therefore, my unfortunate quick conclusion after skimming through it: BS.
The groups werenāt similar, i.e randomization failed so a difference between the groups can impact the result. Itās not surprising as it was a relatively small study.
Brain training have training effects without affecting the underlying physiology that generalizes to other tasks.
Without blinding differences in results can be because itās expected.
The interventions like ketogenic diet have low compliance in studies.
Itās not clear to me how consistent the protocol was between users unlike a drug you just give to participants. Did all of them go through each intervention in the same way, determined in a similar fashion?
I think trials that can be blinded adequately with large enough sample size will address these issues, it just appears thatās oral drugs like pills with a large bankroll, so pharma?
What do you think?
One more good reason to avoid dementiaā¦
āMy family has been devastated by this disease,ā Whitney said in a press statement. āMy mom had 13 brothers and sisters, and 10 died before they were 60 years old. Itās been a plague.ā
Despite inheriting the same mutation, Whitney has reached his late 70s without developing any major memory problems or other symptoms of Alzheimerās disease. To date, he is the only known carrier to escape the condition for many years after its expected onset.
Geoffrey Canet at the French National Centre for Scientific Research became interested in Whitneyās case after having a discussion at a conference with Randall Bateman from Washington University in St. Louis, Missouri, who has been studying Whitney for years.
At the conference, Canet presented his teamās research on the beneficial effects of heat therapy on the brains of mice. Studies in Finland have found that frequent sauna users are 65 per cent less likely to develop Alzheimerās disease than occasional dabblers, which led Canet and his colleague Emmanuel Planel at Laval University in Quebec to study the underlying mechanisms.
Their results piqued Batemanās interest, since he knew Whitney had worked for two decades in the very hot engine rooms of steam-propelled navy ships, starting when he was 18. Bateman discussed the case with Canet and Planel, who were inspired to investigate it further.
Ship engine rooms can reach temperatures of 50Ā°C (122Ā°F) and Whitney was sometimes in them for hours at a time, occasionally having to be hosed down to avoid overheating.
Possibly as a result of this heat exposure, Whitney has unusually high levels of heat shock proteins in his cerebrospinal fluid. Our bodies produce these in response to heat to repair and refold certain other types of proteins that might be damaged by the increased temperature.
Full story: Man destined for Alzheimerās may have been saved by accidental therapy (New Scientist)
On the flip side, heat exhaustion is terrible for brain health (and other components of health).
It would seem like you need to get hot (as I sit at 196F in a sauna currently) but avoid getting too hot. Your article describes borderline too hot situations. But maybe that border is what is needed.
Benchmarks:
My friendās husband was at the local memory care living center ā supposedly the best in the area ā and it is understaffed and awfulā$25000/month, $300000/year
My mother has an aide who has been with her for ten years, living with her in her apartment, while she has declined into dementia. Now 99, still remarkably strong in body, but no mind left. She would ever have survived this well or this long without this remarkable aide. $25/hour, 24x7, $219,000 / year. plus occasional additional people as back up to the main caregiver.
That is a lot of money.
Having just gone through this with my father, and non that long before my FIL, Iāve seen prices in CA and NC.
My father is in a $7k a month place which is not that nice. But it is well staffed and they are all very patient. He may move to a nicer one that is between $6 and $13k - heād probably be $11k. It is less than 10 years old and is rather luxurious in physical structure. Between 10 and 14 ft ceilings to give some perspective.
Sonoma county which is not Marin or South Bay but is not Nebraska either.
Iāve heard $200k per year for in home care so that tracks.
In NC $10k month is pretty common but can be $8k in what is still a new structure but maybe not soaring ceilings.
Not much cheaper in NC but surprisingly a lot more regulated. Not sure what they are doing in CA but rules arenāt abundant for memory care despite there being more rules on a out everything else.
Sorry to be Mr. Skeptical.
Relative Risk Reduction" (RRR); I am only interested in āAbsolute Risk Reductionā (ARR).
Studies almost always headline RRR.
From time to time, I will critique some of them.
If you use ARR, you will be able to cut down on that long list of supplements and drugs that you take. I admit that I havenāt completed this task on all that I take. I did get the shingles vaccine to prevent getting shingles; sorry, not so much for dementia. But then again, maybe every little bit counts. Thatās why I generally get every vaccine on offer. No vaccine study that I have looked at offers more than, charitably described, āmodest resultsā on dementia of any kind.
The study reported 26% to 33% lower risk (RRR) of dementia following RZV. Sounds great at first.
Notes from Aristotle, Opus 4.7, and Gemini. All were in agreement about ARR.
This results in an ARR of 5.28 cases per 1,000 person-years, or approximately a 0.53% absolute risk reduction per year.
Some confounders: The behavioral disposition that drives someone to get every vaccine on offer is itself plausibly protective against dementia (or correlated with things that are: education, income, social engagement, executive function), and that disposition isnāt fully captured by the measured covariates
Industry funding. Funded by GSK, the manufacturer of RZV (Shingrix). Three co-authors are GSK employees with stock options. This does not invalidate findings but warrants scrutiny.
It also sounds great to me in absolute terms. But when assessed over a 30 year period (age 70 to 100?)
Absolute risk reduction is modest: ~5 fewer dementia cases per 1,000 people per year
But over 30 years thatās 150 dementia cases.
Or put another way if 33% lower risk is not worth bothering with is even a 100% lower risk? After all 15 /1000 people is only 1.5% risk each year.
There are studies that remove healthy user bias. Primarily ones from Europe (I am pretty sure there is more than one) that compare groups based on birthdays.
The birthday acted as a randomization equivalent and they compared groups based on that. By memory, these were 2 different vaccines - and the modern Shingrix did better. Better meaning lower rates of AD. And that isnāt compared to nothing but just a less effective vaccine.
Now, sure, the older vaccine could have been harmful compared to no vaccine. These studies were in populations with universal health care and near 100% vaccine uptakes. And as European studies they were mostly on white people with homogenous genetics.
I have a potentially massive issue here. I believe all these studies were on dosing at around 65. Today we are dosing at 50 or lower for some lucky younger folks. When you look at the timeline of damage, we have multiple studies/opinions that show it is a lifetime effect that is accelerated in middle age.
So if you can find a difference in a 65 year old getting a shot with typical 5 year followups, that doesnāt tell you what risk reduction you get with a 30 year disease process for someone getting the shot at 50. I am not a betting man but I would take that bet that you will see more effect with 30 years of disease protection and progression.
So you can hem and haw about relative vs absolute risk reduction but realize you are likely massively underestimating the protection.
I realize no one here is not getting the shingles vaccine but we all know vaccine hesitant people. Do not underestimate the potential effect here. And then throw in the potentially synergy with all the other vaccines. And looking at NNT is just outside the realm of what the average human can compute. NNT is for epidemiologists, not for the average person.
I would take a vaccine for 1 day less in memory care or for one more day remembering my loved ones.
And donāt forget Pneumovax, dtap, flu and RSV. In medicine, I am happy to have gotten more vaccines than most and have probably 20 year streak with flu vaccines since it has been required at our forward thinking hospitals for as long as I can remember. I was influenced by the 1995 study showing less days missed for work by taking the flu shot well in excess of what the flu could account for. Theorizing that the improved immune activity prevented much more than just influenza.
This has probably been linked elsewhere but I didnāt see it in this thread. 55% risk reduction in the 2 years after high dose flu vaccine vs low dose. Are you kidding me?!? And you donāt think vaccines are helpful for preventing dementia?
Oral administration of arginine suppresses AĪ² pathology in animal models of Alzheimerās disease
https://www.sciencedirect.com/science/article/pii/S019701862500155X?via%3Dihub
another reason to take l-citrulline?
To clarify: My main point is that you cannot jump on the bandwagon of every supplement or medication that headlines dramatic risk reduction by using RRR. You cannot possibly take them all. The study I was looking at wasnāt a particularly good study and was funded by the very people who profit from it and researchers who also stood to profit.
This does not mean that I think all studies funded by companies that stand to profit from them, which is quite a large percentage, are wrong.
In this particular supplement a huge industry stands to benefit from promoting it as much as possible regardless of its actual benefits:
" The trade association ā GOED. This is the coordinating body for industry promotion. The Global Organization for EPA and DHA Omega-3s (GOED) was founded in 2006, with roots going back to 2000 when industry leaders petitioned the FDA to establish a heart disease risk reduction claim for omega-3s. Its 200+ members represent the entire supply chain from fisheries and crude oil suppliers to refiners, concentrators and brands. GOED runs AlwaysOmega3s.com to translate the science into consumer-facing language and FatsOfLife.com aimed at healthcare professionals. An āomega-3 coalitionā coordinated through GOED ran a test-market campaign in Charlotte using TV, print, digital, billboard, and PR, and estimated 28,000ā61,000 new omega-3 users came into the category specifically because of that campaign ā boosting fish oil, concentrates, and krill oil sales 2.2ā2.6% per week. This is the clearest documented example of coordinated industry-funded subsidization of category demand. GOED + 2
Not to really disagree at all but how else would a supplement market and ''get the word out" as far as benefits. There really isnāt deep pockets of big pharma.
So to bring supplements to equivalency, they would need to band together. Marketing of any type is potentially an issue of course. But look at the marketing of creatine. Right - there really isnāt any despite a decent amount of literature etc. I see GNC maybe doing something but otherwise, who?
And how many people are missing out on benefits of certain supplements?
If vitamin D had a single pharma manufacturer, how many more people would be taking it?
While the supplement market is huge and there is some advertising, I wouldnāt object to some brands banding together to petition the FDA to have some reasonable claims.
An interesting theory I just came up with for a new Alzheimerās drug targeting existing amyloid plaques:
In this Nature paper it states that lithium orotate reduced amyloid sequestration much more effectively than lithium carbonate. I think a lot of people read this and concluded that carbonate is therefore of no use for Alzheimerās but looking closer at the study it stated that compared to lithium orotate, carbonate significantly sequestered in plaques.
The study implies that this makes orotate better because the orotate form can act freely in the brain. IT is true that this is good information on lithium orotate, but if lithium carbonate is strongly attracted to the plaques this could also be useful for creating drugs that directly target the plaques. Creating a compound that has a drug payload attached to lithium carbonate could be an effective treatment to clear plaques.
āLi was highly concentrated in AĪ² plaques after the administration of LiC, but to a much smaller extent after administration of LiO in both 3xTg and J20 mice (Extended Data Fig. 7c,d). Moreover, LiO, but not LiC, significantly elevated parenchymal Li in the non-plaque fraction in 3xTg and J20 mice (Extended Data Fig. 7e,f). Thus, LiO shows reduced amyloid sequestration relative to LiC and more effectively elevates non-plaque Li in the brain.ā
Source: Lithium deficiency and the onset of Alzheimerās disease | Nature
Research from the Buck Institute reveals that the protective APOE2 variant, already associated with exceptional longevity and reduced Alzheimerās risk, keeps human brain cells genomically stable and resistant to cellular senescence
People who carry the APOE2 version of the apolipoprotein E gene are more likely to live to advanced age and are partly protected against Alzheimerās disease, but scientists have struggled to explain why. A new study from the Buck Institute for Research on Aging, now published in Aging Cell, offers a mechanistic answer: APOE2 helps human neurons keep their DNA intact and resist becoming senescent, a damaged, dysfunctional state that accumulates with age and contributes to neurodegeneration.
The findings shift attention away from APOEās well-known role in cholesterol transport and toward a previously underappreciated function of the gene: shaping how brain cells maintain the integrity of their genome as they age.
āWeāve known for years that APOE2 carriers tend to live longer and have a lower risk of Alzheimerās, but the protective mechanism has been a black box,ā says senior author Lisa M. Ellerby, PhD, professor at the Buck Institute. āOur work shows that APOE2 neurons are better at preventing and repairing DNA damage, and they resist the cellular aging program that drives so much of late-life decline. Our findings point to entirely new therapeutic directions.ā
More:
I like your thinking but i dont think Liāŗ can be a conjugation scaffold. Itās a bare monovalent cation ā with no functional groups, and no covalent chemistry to exploit.
Once LiC dissolves in biological media, you have free Liāŗ and COāĀ²ā». The Liāŗ plaque sequestration is probably ionic: the amyloid matrix is highly charged (anionic), and small cations like Liāŗ accumulate via electrostatic trapping. Thatās a property of the free ion, not something that survives conjugation to a payload.
itās likely that LiC-derived Liāŗ gets trapped more than LiO-derived Liāŗ because of a kinetics/availability issue: LiO has better CNS bioavailability and distributes into parenchyma before ionic equilibrium with plaques is reached.
So LiC is just slower a distributing more widely.
But i could easily be wrong
